Subject‐level matching for imbalance in cluster randomized trials with a small number of clusters

In a cluster randomized controlled trial (RCT), the number of randomized units is typically considerably smaller than in trials where the unit of randomization is the patient. If the number of randomized clusters is small, there is a reasonable chance of baseline imbalance between the experimental and control groups. This imbalance threatens the validity of inferences regarding post‐treatment intervention effects unless an appropriate statistical adjustment is used. Here, we consider application of the propensity score adjustment for cluster RCTs. For the purpose of illustration, we apply the propensity adjustment to a cluster RCT that evaluated an intervention to reduce suicidal ideation and depression. This approach to adjusting imbalance had considerable bearing on the interpretation of results. A simulation study demonstrates that the propensity adjustment reduced well over 90% of the bias seen in unadjusted models for the specifications examined. Copyright © 2013 John Wiley & Sons, Ltd.     

Methods for estimating relative risk in studies of common binary outcomes

Studying the effect of exposure or intervention on a dichotomous outcome is very common in medical research. Logistic regression (LR) is often used to determine such association which provides odds ratio (OR). OR often overestimates the effect size for prevalent outcome data. In such situations, use of relative risk (RR) has been suggested. We propose modifications in Zhang and Yu and Diaz-Quijano methods. These methods were compared with stratified Mantel Haenszel method, LR, log binomial regression (LBR), Zhang and Yu method, Poisson/Cox regression, modified Poisson/Cox regression, marginal probability method, COPY method, inverse probability of treatment weighted LBR, and Diaz-Quijano method. Our proposed modified Diaz-Quijano (MDQ) method provides RR and its confidence interval similar to those estimated by modified Poisson/Cox and LBRs. The proposed modifications in Zhang and Yu method provides better estimate of RR and its standard error as compared to Zhang and Yu method in a variety of situations with prevalent outcome. The MDQ method can be used easily to estimate the RR and its confidence interval in the studies which require reporting of RRs. Regression models which directly provide the estimate of RR without convergence problems such as the MDQ method and modified Poisson/Cox regression should be preferred.     

Robust inference from multiple test statistics via permutations: a better alternative to the single test statistic approach for randomized trials

Formal inference in randomized clinical trials is based on controlling the type I error rate associated with a single pre‐specified statistic. The deficiency of using just one method of analysis is that it depends on assumptions that may not be met. For robust inference, we propose pre‐specifying multiple test statistics and relying on the minimum p‐value for testing the null hypothesis of no treatment effect. The null hypothesis associated with the various test statistics is that the treatment groups are indistinguishable. The critical value for hypothesis testing comes from permutation distributions. Rejection of the null hypothesis when the smallest p‐value is less than the critical value controls the type I error rate at its designated value. Even if one of the candidate test statistics has low power, the adverse effect on the power of the minimum p‐value statistic is not much. Its use is illustrated with examples. We conclude that it is better to rely on the minimum p‐value rather than a single statistic particularly when that single statistic is the logrank test, because of the cost and complexity of many survival trials. Copyright © 2013 John Wiley & Sons, Ltd.     

Improving precision and power in randomized trials with a two-stage study design: Stratification using clustering method

In a randomized controlled trial (RCT), it is possible to improve precision and power and reduce sample size by appropriately adjusting for baseline covariates. There are multiple statistical methods to adjust for prognostic baseline covariates, such as an ANCOVA method. In this paper, we propose a clustering-based stratification method for adjusting for the prognostic baseline covariates. Clusters (strata) are formed only based on prognostic baseline covariates, not outcome data nor treatment assignment. Therefore, the clustering procedure can be completed prior to the availability of outcome data. The treatment effect is estimated in each cluster, and the overall treatment effect is derived by combining all cluster-specific treatment effect estimates. The proposed implementation of the procedure is described. Simulations studies and an example are presented.     

Decision‐making in a phase II clinical trial: a new approach combining Bayesian and frequentist concepts

The aim of a phase II clinical trial is to decide whether or not to develop an experimental therapy further through phase III clinical evaluation. In this paper, we present a Bayesian approach to the phase II trial, although we assume that subsequent phase III clinical trials will have standard frequentist analyses. The decision whether to conduct the phase III trial is based on the posterior predictive probability of a significant result being obtained. This fusion of Bayesian and frequentist techniques accepts the current paradigm for expressing objective evidence of therapeutic value, while optimizing the form of the phase II investigation that leads to it. By using prior information, we can assess whether a phase II study is needed at all, and how much or what sort of evidence is required. The proposed approach is illustrated by the design of a phase II clinical trial of a multi‐drug resistance modulator used in combination with standard chemotherapy in the treatment of metastatic breast cancer. Copyright © 2005 John Wiley & Sons, Ltd     

Multicollinearity and financial constraint in investment decisions: a Bayesian generalized ridge regression

This paper addresses the investment decisions considering the presence of financial constraints of 373 large Brazilian firms from 1997 to 2004, using panel data. A Bayesian econometric model was used considering ridge regression for multicollinearity problems among the variables in the model. Prior distributions are assumed for the parameters, classifying the model into random or fixed effects. We used a Bayesian approach to estimate the parameters, considering normal and Student t distributions for the error and assumed that the initial values for the lagged dependent variable are not fixed, but generated by a random process. The recursive predictive density criterion was used for model comparisons. Twenty models were tested and the results indicated that multicollinearity does influence the value of the estimated parameters. Controlling for capital intensity, financial constraints are found to be more important for capital-intensive firms, probably due to their lower profitability indexes, higher fixed costs and higher degree of property diversification.     

The Rheumatoid Arthritis Drug Development Model: a case study in Bayesian clinical trial simulation

The development of a new drug is a major undertaking and it is important to consider carefully the key decisions in the development process. Decisions are made in the presence of uncertainty and outcomes such as the probability of successful drug registration depend on the clinical development programmme. The Rheumatoid Arthritis Drug Development Model was developed to support key decisions for drugs in development for the treatment of rheumatoid arthritis. It is configured to simulate Phase 2b and 3 trials based on the efficacy of new drugs at the end of Phase 2a, evidence about the efficacy of existing treatments, and expert opinion regarding key safety criteria. The model evaluates the performance of different development programmes with respect to the duration of disease of the target population, Phase 2b and 3 sample sizes, the dose(s) of the experimental treatment, the choice of comparator, the duration of the Phase 2b clinical trial, the primary efficacy outcome and decision criteria for successfully passing Phases 2b and 3. It uses Bayesian clinical trial simulation to calculate the probability of successful drug registration based on the uncertainty about parameters of interest, thereby providing a more realistic assessment of the likely outcomes of individual trials and sequences of trials for the purpose of decision making. In this case study, the results show that, depending on the trial design, the new treatment has assurances of successful drug registration in the range 0.044–0.142 for an ACR20 outcome and 0.057–0.213 for an ACR50 outcome. Copyright © 2009 John Wiley & Sons, Ltd.     

Classification rules for identifying individuals at high risk of developing myocardial infarction based on ApoB,ApoA1 and the ratio were determined using a Bayesian approach

We have developed a new approach to determine the threshold of a biomarker that maximizes the classification accuracy of a disease. We consider a Bayesian estimation procedure for this purpose and illustrate the method using a real data set. In particular, we determine the threshold for Apolipoprotein B (ApoB), Apolipoprotein A1 (ApoA1) and the ratio for the classification of myocardial infarction (MI). We first conduct a literature review and construct prior distributions. We then develop classification rules based on the posterior distribution of the location and scale parameters for these biomarkers. We identify the threshold for ApoB and ApoA1, and the ratio as 0.908 (gram/liter), 1.138 (gram/liter) and 0.808, respectively. We also observe that the threshold for disease classification varies substantially across different age and ethnic groups. Next, we identify the most informative predictor for MI among the three biomarkers. Based on this analysis, ApoA1 appeared to be a stronger predictor than ApoB for MI classification. Given that we have used this data set for illustration only, the results will require further investigation for use in clinical applications. However, the approach developed in this article can be used to determine the threshold of any continuous biomarker for a binary disease classification.     

Bayesian analysis of contingency tables: a simulation and graphics-based approach

In this paper we present a simulation and graphics-based model checking and model comparison methodology for the Bayesian analysis of contingency tables. We illustrate the approach by testing the hypotheses of independence and symmetry on complete and incomplete simulated tables.     

Longitudinal profiles of bounded outcome scores as predictors for disease activity in rheumatoid arthritis patients: a joint modeling approach

A variety of statistical approaches have been suggested in the literature for the analysis of bounded outcome scores (BOS). In this paper, we suggest a statistical approach when BOSs are repeatedly measured over time and used as predictors in a regression model. Instead of directly using the BOS as a predictor, we propose to extend the approaches suggested in [16 E. Lesaffre, D. Rizopoulos, and R. Tsonaka, The logistics-transform for bounded outcome scores, Biostatistics 8 (2007), pp. 72–85. doi: 10.1093/biostatistics/kxj034[Crossref], [PubMed], [Web of Science ®] , [Google Scholar],21 M. Molas and E. Lesaffre, A comparison of the three random effects approaches to analyse repeated bounded outcome scores with an application in a stroke revalidation study, Stat. Med. 27 (2008), pp. 6612–6633. doi: 10.1002/sim.3432[Crossref], [PubMed], [Web of Science ®] , [Google Scholar],28 R. Tsonaka, D. Rizopoulos, and E. Lesaffre, Power and sample size calculations for discrete bounded outcome scores, Stat. Med. 25 (2006), pp. 4241–4252. doi: 10.1002/sim.2679[Crossref], [PubMed], [Web of Science ®] , [Google Scholar]] to a joint modeling setting. Our approach is illustrated on longitudinal profiles of multiple patients’ reported outcomes to predict the current clinical status of rheumatoid arthritis patients by a disease activities score of 28 joints (DAS28). Both a maximum likelihood as well as a Bayesian approach is developed.     

Comparison of dichotomized and distributional approaches in rare event clinical trial design: a fixed Bayesian design

This research was motivated by our goal to design an efficient clinical trial to compare two doses of docosahexaenoic acid supplementation for reducing the rate of earliest preterm births (ePTB) and/or preterm births (PTB). Dichotomizing continuous gestational age (GA) data using a classic binomial distribution will result in a loss of information and reduced power. A distributional approach is an improved strategy to retain statistical power from the continuous distribution. However, appropriate distributions that fit the data properly, particularly in the tails, must be chosen, especially when the data are skewed. A recent study proposed a skew-normal method. We propose a three-component normal mixture model and introduce separate treatment effects at different components of GA. We evaluate operating characteristics of mixture model, beta-binomial model, and skew-normal model through simulation. We also apply these three methods to data from two completed clinical trials from the USA and Australia. Finite mixture models are shown to have favorable properties in PTB analysis but minimal benefit for ePTB analysis. Normal models on log-transformed data have the largest bias. Therefore we recommend finite mixture model for PTB study. Either finite mixture model or beta-binomial model is acceptable for ePTB study.     

Discrete and continuous bivariate lifetime models in presence of cure rate: a comparative study under Bayesian approach

The modeling and analysis of lifetime data in which the main endpoints are the times when an event of interest occurs is of great interest in medical studies. In these studies, it is common that two or more lifetimes associated with the same unit such as the times to deterioration levels or the times to reaction to a treatment in pairs of organs like lungs, kidneys, eyes or ears. In medical applications, it is also possible that a cure rate is present and needed to be modeled with lifetime data with long-term survivors. This paper presented a comparative study under a Bayesian approach among some existing continuous and discrete bivariate distributions such as the bivariate exponential distributions and the bivariate geometric distributions in presence of cure rate, censored data and covariates. In presence of lifetimes related to cured patients, it is assumed standard mixture cure rate models in the data analysis. The posterior summaries of interest are obtained using Markov Chain Monte Carlo methods. To illustrate the proposed methodology two real medical data sets are considered.     

Joint models for mixed categorical outcomes: a study of HIV risk perception and disease status in Mozambique

Two types of bivariate models for categorical response variables are introduced to deal with special categories such as ‘unsure’ or ‘unknown’ in combination with other ordinal categories, while taking additional hierarchical data structures into account. The latter is achieved by the use of different covariance structures for a trivariate random effect. The models are applied to data from the INSIDA survey, where interest goes to the effect of covariates on the association between HIV risk perception (quadrinomial with an ‘unknown risk’ category) and HIV infection status (binary). The final model combines continuation-ratio with cumulative link logits for the risk perception, together with partly correlated and partly shared trivariate random effects for the household level. The results indicate that only age has a significant effect on the association between HIV risk perception and infection status. The proposed models may be useful in various fields of application such as social and biomedical sciences, epidemiology and public health.